Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis.
Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis1. These lesions are precursors for blood cancers2-6, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.
View details for DOI 10.1038/s41586-023-05806-1
View details for PubMedID 37046083
View details for PubMedCentralID 4624443
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Anti-tumor NAMPT inhibitor, KPT-9274, mediates gender-dependent murine anemia and nephrotoxicity by regulating SIRT3-mediated SOD deacetylation.
Journal of hematology & oncology
2021; 14 (1): 101
KPT-9274 is a phase 1 first-in-class dual PAK4/NAMPT inhibitor for solid tumor and non-Hodgkin's lymphoma. It demonstrates pre-clinical efficacy toward a broad spectrum of acute myeloid leukemia (AML) subtypes by inhibiting NAMPT-dependent NAD+ production. NAMPT is the rate-limiting enzyme in the salvage metabolic pathway leading to NAD+ generation. Tumor cells which are deficient in de novo pathway enzyme NAPRT1 are addicted to NAMPT. In clinical trials, treatment with NAMPT inhibitors resulted in dose-limiting toxicities. In order to dissect the mechanism of toxicity, mice were treated with KPT-9274 and resulting toxicities were characterized histopathologically and biochemically. KPT-9274 treatment caused gender-dependent stomach and kidney injuries and anemia. Female mice treated with KPT-9274 had EPO deficiency and associated impaired erythropoiesis. KPT-9274 treatment suppressed SIRT3 expression and concomitantly upregulated acetyl-manganese superoxide dismutase (MnSOD) in IMCD3 cells, providing a mechanistic basis for observed kidney toxicity. Importantly, niacin supplementation mitigated KPT-9274-caused kidney injury and EPO deficiency without affecting its efficacy. Altogether, our study delineated the mechanism of KPT-9274-mediated toxicity and sheds light onto developing strategies to improve the tolerability of this important anti-AML inhibitor.
View details for DOI 10.1186/s13045-021-01107-0
View details for PubMedID 34187548
Targeting DNA damage repair functions of two histone deacetylases, HDAC8 and SIRT6, sensitizes acute myeloid leukemia to NAMPT inhibition.
Clinical cancer research : an official journal of the American Association for Cancer Research
PURPOSE: Nicotinamide phosphoribosyltransferase (NAMPT) inhibitors are currently in development, but may be limited as a single agent therapy due to compound-specific toxicity and cancer metabolic plasticity allowing resistance development. To potentially lower the doses of NAMPT inhibitors required for therapeutic benefit against acute myeloid leukemia (AML), we performed a genome-wide CRISPRi screen to identify rational disease-specific partners for a novel NAMPT inhibitor, KPT-2974.EXPERIMENTAL DESIGN: Cell lines and primary cells were analyzed for cell viability, self-renewal and responses at RNA and protein levels with loss-of-function approaches and pharmacologic treatments. In vivo efficacy of combination therapy was evaluated with a xenograft model.RESULTS: We identified two histone deacetylases, HDAC8 and SIRT6, whose knockout conferred synthetic lethality with KPT-9274 in AML. Furthermore, HDAC8-specific inhibitor, PCI-34051, or clinical Class I HDAC inhibitor, AR-42, in combination with KPT-9274, synergistically decreased the survival of AML cells in a dose-dependent manner. AR-42/KPT-9274 co-treatment attenuated colony-forming potentials of patient cells while sparing healthy hematopoietic cells. Importantly, combined therapy demonstrated promising in vivo efficacy compared with KPT-9274 or AR-42 monotherapy. Mechanistically, genetic inhibition of SIRT6 potentiated the effect of KPT-9274 on PARP-1 suppression by abolishing mono-ADP ribosylation. AR-42/KPT-9274 co-treatment resulted in synergistic attenuation of homologous recombination (HR) and nonhomologous end joining (NHEJ) pathways in cell lines and leukemia initiating cells (LICs).CONCLUSIONS: Our findings provide evidence that HDAC8 inhibition- or shSIRT6-induced DNA repair deficiencies are potently synergistic with NAMPT targeting, with minimal toxicity towards normal cells, providing a rationale for a novel-novel combination-based treatment for AML.
View details for DOI 10.1158/1078-0432.CCR-20-3724
View details for PubMedID 33542077
Insights into clonal hematopoiesis and its relation to cancer risk.
Current opinion in genetics & development
2021; 66: 63–69
In the multi-hit model of carcinogenesis, a precancerous state often precedes overt malignancy. Identification of these states has been of great interest as they allow for early identification of at-risk individuals before the appearance of a future cancer. One such condition has recently been described for blood cancers: Clonal Hematopoiesis of Indeterminate Potential (CHIP). Recent research advances have elucidated the risk of progression of CHIP to myeloid malignancies, its potential as a precursor for non-myeloid blood cancers, and its association with non-hematological cancers. Understanding the evolution of CHIP to hematological malignancy may help identify CHIP carriers at high risk of transformation and lead to the development of targeted therapies that can be deployed preemptively.
View details for DOI 10.1016/j.gde.2020.12.004
View details for PubMedID 33422951